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Anti-HIV Natural Products from the plants Destributed in the Northern Part of Japan

来自日本北部植物的抗 HIV 天然产物

基本信息

批准号：
11694321
负责人：
KASHIWADA Yoshiki
金额：
$ 1.73万
依托单位：
Niigata College of Pharmacy
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11694321/
关键词：
Anti-HIV betulinic acid betulin ursolic acid triterpenoids

项目摘要

As a part of the structure-activity relationship study of the potent anti-HIV agent 3-Ο-(3', 3'-dimenthyl)-succinyl-betulinic acid(DSB), 3-Alkylamido-3-deoxy-betulinic acids were synthesized and evaluated for anti-HIV activity, 3-αDiglycorylamide-3-deoxy-betulinic acid demonstrated relatively potent anti-HIV activity(EC_<50> 0.24 μM, TI 728). However, replacing the ester group at C-3 in DSB and its analogues with an amido group yielded inactive or much less potent compounds against HIV replication, indicating that the ester group at C-3 in is essential for potent anti-HIV activity.Four isomers of 3,28-di-Ο-(dimethylsuccinyl)-betulin were prepared and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. 3-Ο-(3', 3'-Dimethylsuccinyl)-28-Ο-(2", 2"-dimethylsuccinyl)-betulin was the most potent anti-HIV compound with an EC_<50> value of 0.00087 μM and a TI value of 42,400.3-Ο-Acyl-ursolic acids were prepared and evaluated their anti-HIV activities, based on our previous finding that 3-Ο-acyl-betulinic acid and -oleanolic acid, especially 3-Ο-(3', 3'-dimethyl)-succinyl-betulinic acid, and -oleanolic acid demonstrated potent anti-HIV activities(EC_<50> < 0.00035 and 0.00086 μM, respectively, therapeutic index(TI) > 20,000 and 22,326, respectively), as well as the fact that ursolic acid(6)showed similar level of anti-HIV activity(EC_<50> 4,4μM)to that of oleanolic acid(EC_<50> 3.7 μM), though it was slightly toxic(IC_<50> 14.3 μM, T.I.3.3). 3-Ο-Diglycoryl-ursolic acid demonstrated relatively potent anti-HIV activity with an EC_<50> 0.31 μM, and a TI of 155.5. In contrast, 3-Ο-(3', 3'-dimethylsuccinyl)-ursolic acid, corresponding to the extremely potent anti-HIV betulinic acid and oleanolic acid derivatives displayed only a weak anti-HIV activity(EC_<50> 2.1μM, T.I.23.6).

作为高效抗艾滋病药物3-Ο-(3‘，3’-二甲基)-琥珀酰白桦酸构效关系研究的一部分，合成了3-烷基酰胺-3-脱氧-白桦酸，并对其抗艾滋病活性进行了评价，3-α二甘油酰胺-3-脱氧-白桦酸表现出较强的抗艾滋病活性(EC_&lt；50&GT；0.24μM，TI728)。然而，用氨基取代DSB及其类似物中C-3位的酯基得到的化合物抗HIV-1复制活性较弱，表明C-3位的酯基团是有效抗HIV活性所必需的。制备了4种3，28-二Ο-(二甲基琥珀酰基)-桦木醇异构体，并评价了它们在H9淋巴细胞中抗HIV-1复制的活性。3-Ο-(3‘，3’-二甲基丁二酸基)-28-Ο-(2“，2”-二甲基丁二酸基)-桦木醇是最有效的抗艾滋病毒化合物，其EC50和GT；根据我们先前的研究发现，3-μ-(3‘，3’-二甲基)-琥珀酰白桦酸和-齐墩果酸，特别是3-Ο-(3‘，3’-二甲基)-琥珀酰白桦酸和-齐墩果酸表现出较强的抗艾滋病毒活性(EC_&lt；50&gt；&lt；0.00035和0.00086ΟM，治疗指数(TI)和GT；)，并评价了它们的抗艾滋病毒活性(EC_&lt；50&gt；&lt；0.00035和0.00086Ο-M，治疗指数(TI)和GT；2,000和22,326)，以及乌索酸(6)表现出与齐墩果酸(EC_&lt；50&gt；3.7μM)相似的抗艾滋病毒活性(EC_&lt；50&gt；4，4μM)，尽管它有轻微的毒性(IC_&lt；50&gt；14.3μM，T.I.3.3)。3-Ο-二甘草酰-熊果酸具有较强的抗艾滋病毒活性，其EC50和TI值分别为0.31μM和155.5。相反，3-Ο-(3‘，3’-二甲基琥珀酰基)-熊果酸，对应于极强的抗艾滋病毒白桦酸和齐墩果酸衍生物，只显示出弱的抗艾滋病毒活性(EC_&lt；50&gt；2.1μM，T.I.23.6)。